Insulin resistance is a pathologic condition which requires an excess amount of insulin over the normal amount for gaining a variety of actions of insulin at the level of cells, organs and individuals. This pathologic condition is a state meaning decrease of the insulin sensitivity in liver, skeletal muscle and fat tissue and characteristic in type II diabetes mellitus with failure of insulin secretion. Insulin resistance is much involved in formation of a pathologic condition of lifestyle-related diseases such as hypertension or hyperlipemia in addition to diabetes mellitus and impaired glucose tolerance, and its improvement is becoming clinically more important.
As drugs which can possibly be used as insulin resistance-improving drugs inhibiting insulin resistance, compounds which have a γ-agonist activity of peroxisome proliferator-activated receptor (PPAR)(hereinafter referred to as “PPAR-γ activation promoting compound”), which is a nuclear receptor, have been known and some of them have been employed for type II diabetes mellitus. These compounds have a blood sugar-lowering effect in addition to lipid metabolism-improving effect.
As for PPAR-γ activation promoting compounds, thiazolidine-type compounds and non-thiazolidine-type compounds are known. The thiazolidine-type compound includes troglitazone, pioglitazone, rosiglitazone, CS-011, and the like; and the non-thiazolidine-type compound includes TAK-559; FK-614, and the like.
It has been considered that these insulin resistance-improving drugs primarily act on adipocytes through PPARγ to accelerate differentiation of the adipocytes and inhibit an insulin resistance causative factor such as TNF-α to improve the insulin resistance. Details are not clear.
In this connection, the first launched insulin resistance improving drug in the world was a thiazolidine-type compound troglitazone, but this was withdrawn because of occurrence of serious hepatic disturbance. Subsequently, the same thiazolidine compounds, pioglitazone and rosiglitazone, were developed and at present these two drugs have been used oversea as insulin resistance improving drugs; in Japan, pioglitazone alone has been used.
However, there was a problem in the insulin resistance improving drugs since they have other side-effects, i.e., edema, heart enlargement, anemia, and soon, particularly edema. That is, in pioglitazone, rosiglitazone and troglitazone, the side-effects such as edema and anemia have been observed in several percentage, and in pioglitazone congestive heart failure has been recognized. This is one of the reasons why they are not so used domestically in Japan though they have a high usefulness as insulin resistance-improving drugs.
Such edema as a side-effect has been observed in all of the so far known thiazolidine-type compounds under development; when the edema occurs as side effect, the administration has to be stopped in some cases, and in another case a diuretic is required; thus, these have big problems in using as drugs.
As mentioned above, the insulin resistance-improving drugs have problems of the side effects such as edema, heart enlargement and anemia. Thus, the purpose of the invention is to provide a technique for reducing such side effects.